Transcriptome profiling of the aging fly brain
Ontology highlight
ABSTRACT:
ORGANISM(S): Drosophila melanogaster
PROVIDER: GSE107049 | GEO | 2019/05/17
REPOSITORIES: GEO
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Project description:This SuperSeries is composed of the following subset Series: GSE24992: Drosophila brain microRNA expression with age: miRNA profiling GSE25007: Drosophila brain gene expression with age: mRNA profiling GSE25008: Drosophila brain gene expression between wildtype and miR-34 null flies Refer to individual Series. Aging is the most prominent risk factor for human neurodegenerative disease, but underlying mechanisms that connect two processes are less well characterized. With age, the brain undergoes functional decline and perhaps degeneration. Such decline may not just contribute to normal aging, but also enhance susceptibility to and progression of age-related neurodegenerative diseases. Therefore, defining intrinsic factors and pathways that underline the normal integrity of the adult nervous system may lead to insights that potentially link aging and neurodegeneration. Here, we report a highly conserved microRNA (miRNA), miR-34, as a modulator of aging and neurodegeneration. Using Drosophila, we show that fly miR-34 expression is brain-enriched and strikingly upregulated with age. Functional studies reveal that, whereas animals without miR-34 are normal as young adults, upon aging, they gradually show late-onset deficits characteristic of accelerated brain aging; these include a transcriptional signature of aged animals, coupled with rapid functional decline, loss of brain integrity, followed by a catastrophic decline in adult viability. Moreover, upregulation of miR-34 protects against neurodegeneration induced by pathogenic human polyglutamine (polyQ) disease protein. We next reveal a dramatic effect of miR-34 to silence the Eip74EF gene of steroid hormone pathways in the adult, which is crucial to maintain the normal aging. Collectively, these data define a miR-34-mediated mechanism that specifically affects long-term integrity of the adult nervous system. miR-34 function in Drosophila may thus present a link that functionally connects aging and neurodegeneration. Our studies implicate essential roles of miRNA- dependent pathways in maintenance of the adult brain, disease pathogenesis and healthy aging.
2011-12-23 | E-GEOD-25009 | biostudies-arrayexpress
Project description:Aging leads to a progressive deterioration in brain function, which will eventually result in cognitive decline and can develop into a dementia. The mechanisms underlying pathological cognitive decline in aging are still poorly understood. The peripheral immune system, as well as the meningeal lymphatic vasculature and the immune cells residing in the brain and meninges, are all affected by aging. Moreover, recent studies have linked the dysfunction of the meningeal lymphatic system and peripheral immunity to accelerated brain aging. We hypothesized that an age-related reduction in CCR7-dependent immune cell egress through the lymphatic vasculature mediates some aspects of aging-associated brain dysfunction, leading to cognitive decline and potentially exacerbating neurodegenerative diseases. Here, we report a reduction in CCR7 expression by meningeal T cells in aged mice and its associated increase in meningeal T-regulatory cells. Hematopoietic CCR7 deficiency mimicked the aging-associated changes in meningeal T cells and led to cognitive impairment. Interestingly, CCR7-deficient mice also presented impaired brain glymphatic function and showed increased amyloid beta (A) deposition when crossed with the 5xFAD transgenic mouse model of Alzheimer’s disease (AD). These results show that the aging-associated decrease in CCR7 expression impacts meningeal immunity, affects different aspects of brain function and exacerbates brain A pathology, highlighting its potential as a pathogenic mechanism for cognitive decline in aging and AD.
2021-03-22 | GSE163725 | GEO
Project description:Age-related cognitive decline is a serious health concern in our aging society. Decreased cognitive function observed during healthy brain aging is most likely caused by changes in brain connectivity and synaptic dysfunction in particular brain regions. Here we show that aged C57BL/6J wildtype mice have hippocampus-dependent spatial memory impairments. To identify the molecular mechanisms that are relevant to these memory deficits we investigated the temporal profile of mouse hippocampal synaptic proteome changes at 20, 40, 50, 60, 70, 80, 90 and 100 weeks of age. Extracellular matrix proteins were the only group of proteins that showed a robust and progressive upregulation over time. This was confirmed by immunoblotting and histochemical analysis, indicating that the increased levels of hippocampal extracellular matrix may limit synaptic plasticity as a potential cause of age-related cognitive decline. In addition, we observed that stochasticity in synaptic protein expression increased with age, in particular for proteins that were previously linked with various neurodegenerative diseases, whereas low variance in expression was observed for proteins that play a basal role in neuronal function and synaptic neurotransmission. Together, our findings show that both specific changes and increased variance in synaptic protein expression are associated with aging and may underlie reduced synaptic plasticity and impaired cognitive performance at old age.
2014-09-10 | PXD001135 | Pride
Project description:Aging is the primary risk factor for most neurodegenerative diseases, including Alzheimer's disease. Major hallmarks of brain aging include neuroinflammation/immune activation and reduced neuronal health/function. These processes contribute to cognitive dysfunction (a key risk factor for Alzheimer's disease), but their upstream causes are incompletely understood. Age-related increases in transposable element (TE) transcripts might contribute to reduced cognitive function with brain aging, as the reverse transcriptase inhibitor 3TC reduces inflammation in peripheral tissues and TE transcripts have been linked with tau pathology in Alzheimer's disease. However, the effects of 3TC on cognitive function with aging have not been investigated. Here, in support of a role for TE transcripts in brain aging/cognitive decline, we show that 3TC: (a) improves cognitive function and reduces neuroinflammation in old wild-type mice; (b) preserves neuronal health with aging in mice and Caenorhabditis elegans; and (c) enhances cognitive function in a mouse model of tauopathy. We also provide insight on potential underlying mechanisms, as well as evidence of translational relevance for these observations by showing that TE transcripts accumulate with brain aging in humans, and that these age-related increases intersect with those observed in Alzheimer's disease. Collectively, our results suggest that TE transcript accumulation during aging may contribute to cognitive decline and neurodegeneration, and that targeting these events with reverse transcriptase inhibitors like 3TC could be a viable therapeutic strategy.
2023-03-23 | GSE213848 | GEO
Project description:Cognitive decline is a common pathological outcome during aging, with an ill-defined cellular or molecular basis. Among the cellular changes observed with age are alterations to neuronal plasticity, changes in the glial compartment and the decline of the neurogenic niche. In the recent years, the concept of inflammaging, defined as a low-grade inflammation increasing with age, has emerged as a nexus for age-related diseases. This increase of basal inflammation is also observed in the central nervous system. While not classically considered a neurological cell type, infiltrating T cells increase in the brain with age, and may be responsible for amplification of inflammatory cascades and disruptions to the neurogenic niche. Recently, a small resident population of regulatory T cells has been identified in the brain, and the capacity of IL2-mediated expansion of this population to counter neuroinflammatory disease has been demonstrated. Here we test a brain-specific IL2 delivery system for the prevention of neurological decline in aging mice. We identify the molecular hallmarks of aging in the brain glial compartments, and identify partial restoration of this signature through IL2 treatment. At a behavioral level, brain IL2 delivery prevented the age-induced defect in learned memory formation during maze tests, without improving the general decline in motor skill or novelty-seeking behavior. These results identify immune modulation as a potential path to preserving cognitive function for healthy ageing.
2022-07-01 | GSE190486 | GEO
Project description:Brain aging is a physiological process associated with physical and cognitive decline; however, in both humans and animals, it that can be regarded as a risk factor for neurodegenerative disorders, such as Alzheimer’s disease. Among several brain regions, hippocampus appears to be more susceptible to detrimental effects of aging. Hippocampus belongs to limbic system and is mainly involved in declarative memories and context-dependent spatial-learning, whose integrity are compromised in an age-dependent manner. In the present work, taking advantage of liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics, we sought to identify proteins differentially expressed in the hippocampus of the aged grazing milk cows. Our exploratory findings showed that 112 proteins were significantly altered in old cattle, when compared to the adult controls, and functional clusterization highlighted their involvement in processes such as myelination, synaptic vesicle, metabolism, and calcium-related pathways. Overall, the present paving the way for the future studies, aimed at better characterizing the role of such a subcortical brain region in the age-dependent cognitive decline across mammals, and identifying early aging markers in farming cattle
2023-10-24 | PXD044404 | Pride
Project description:The decline of brain function during aging is associated with epigenetic changes, including DNA methylation. Lifestyle interventions can improve brain function during aging, but their influence on age-related epigenetic changes is unknown. Using genome-wide DNA methylation sequencing, we here show that environmental enrichment counteracted age-related DNA methylation changes in the hippocampal dentate gyrus of mice. Specifically, environmental enrichment prevented the aging-induced CpG hypomethylation at target sites of the methyl-CpG-binding protein Mecp2, which is known to control neuronal functions. The genes at which environmental enrichment counteracted aging effects have described roles in neuronal plasticity, neuronal cell communication and adult hippocampal neurogenesis and are dysregulated with age-related cognitive decline in the human brain. Our results highlight the rejuvenating effects of environmental enrichment at the level of DNA methylation and give molecular insights into the specific aspects of brain aging that can be counteracted by lifestyle interventions.
2020-12-31 | GSE138368 | GEO
Project description:The decline of brain function during aging is associated with epigenetic changes, including DNA methylation. Lifestyle interventions can improve brain function during aging, but their influence on age-related epigenetic changes is unknown. Using genome-wide DNA methylation sequencing, we here show that experiencing a stimulus-rich environment counteracted age-related DNA methylation changes in the hippocampal dentate gyrus of mice. Specifically, environmental enrichment prevented the aging-induced CpG hypomethylation at target sites of the methyl-CpG-binding protein Mecp2, which is known to control neuronal functions. The genes at which environmental enrichment counteracted aging effects have described roles in neuronal plasticity, neuronal cell communication and adult hippocampal neurogenesis and are dysregulated with age-related cognitive decline in the human brain. Our results highlight the rejuvenating effects of environmental enrichment at the level of DNA methylation and give molecular insights into the specific aspects of brain aging that can be counteracted by lifestyle interventions.
2021-03-31 | GSE171235 | GEO
Project description:The decline of brain function during aging is associated with epigenetic changes, including DNA methylation. Lifestyle interventions can improve brain function during aging, but their influence on age-related epigenetic changes is unknown. Using genome-wide DNA methylation sequencing, we here show that experiencing a stimulus-rich environment counteracted age-related DNA methylation changes in the hippocampal dentate gyrus of mice. Specifically, environmental enrichment prevented the aging-induced CpG hypomethylation at target sites of the methyl-CpG-binding protein Mecp2, which is known to control neuronal functions. The genes at which environmental enrichment counteracted aging effects have described roles in neuronal plasticity, neuronal cell communication and adult hippocampal neurogenesis and are dysregulated with age-related cognitive decline in the human brain. Our results highlight the rejuvenating effects of environmental enrichment at the level of DNA methylation and give molecular insights into the specific aspects of brain aging that can be counteracted by lifestyle interventions.
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Project description:The decline of brain function during aging is associated with epigenetic changes, including DNA methylation. Lifestyle interventions can improve brain function during aging, but their influence on age-related epigenetic changes is unknown. Using genome-wide DNA methylation sequencing, we here show that experiencing a stimulus-rich environment counteracted age-related DNA methylation changes in the hippocampal dentate gyrus of mice. Specifically, environmental enrichment prevented the aging-induced CpG hypomethylation at target sites of the methyl-CpG-binding protein Mecp2, which is known to control neuronal functions. The genes at which environmental enrichment counteracted aging effects have described roles in neuronal plasticity, neuronal cell communication and adult hippocampal neurogenesis and are dysregulated with age-related cognitive decline in the human brain. Our results highlight the rejuvenating effects of environmental enrichment at the level of DNA methylation and give molecular insights into the specific aspects of brain aging that can be counteracted by lifestyle interventions.
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